Inhibition of the immunoproteasome modulates innate immunity to ameliorate muscle pathology of dysferlin-deficient BlAJ mice.

Muscle repair in dysferlinopathies is defective. Although macrophage (Mø)-rich infiltrates are prominent in damaged skeletal muscles of patients with dysferlinopathy, the contribution of the immune system to the disease pathology remains to be fully explored. Numbers of both pro-inflammatory M1 Mø and effector T cells are increased in muscle of dysferlin-deficient BlAJ mice. In addition, symptomatic BlAJ mice have increased muscle production of immunoproteasome. In vitro analyses using bone marrow-derived Mø of BlAJ mice show that immunoproteasome inhibition results in C3aR1 and C5aR1 downregulation and upregulation of M2-associated signaling. Administration of immunoproteasome inhibitor ONX-0914 to BlAJ mice rescues muscle function by reducing muscle infiltrates and fibro-adipogenesis. These findings reveal an important role of immunoproteasome in the progression of muscular dystrophy in BlAJ mouse and suggest that inhibition of immunoproteasome may produce therapeutic benefit in dysferlinopathy.

Use of Diode Laser for Lip Repositioning, Evolution of the Conventional Technique. A Case Report.

INTRODUCTION: LipStaT® lip repositioning surgery using a diode laser for the management of gummy smiles offers promising and consistent long-term results. OBJECTIVE: To describe the technique through a clinical case, including its indications, preoperative evaluation, surgical approach, and recommendations after the intervention. CASE REPORT: A 29-year-old woman with excessive gingival display (EGD) of 4 mm when smiling; the LipStaT® technique was performed with a 940 nm diode laser to remove a strip of mucosa by ablating the epithelial tissue, and thus, achieve aesthetic, harmonic and functional results. The inflammation and postoperative pain were treated with the diode laser assisted lymphatic drainage technique. After follow-up, a satisfactory tissue response was observed, and no pain or inflammation was reported. CONCLUSION: The use of a 940 nm diode laser proved to be an effective treatment option for patients with a gummy smile, allowing control of intraoperative bleeding and improvement of the healing process obtaining predictable long-term results.

The Dural Dark-Side Approach for falcine and tentorial meningioma: A surgical series of five patients.

INTRODUCTION: Falcine or tentorial meningioma can be complex to resect. When large meningiomas are located in eloquent areas, a direct ipsilateral surgical approach may cause brain injury and postoperative neurological deficits. In this series, 5 patients were surgically treated using a contralateral transfalcine or transtentorial approach to minimize brain retraction. This strategy was called the Dural Dark-Side Approach (DDSA). The aim was to analyze the quality of tumor resection and postoperative outcome. MATERIAL AND METHODS: In our department, from June 2018 to January 2020, 5 patients underwent microsurgical DDSA for resection of 4 falcine and 1 tentorial meningioma. All tumors were selected on the following two criteria: large>40mm diameter tumor, with surrounding functional cortex. Clinical and radiologic data were retrospectively analyzed. RESULTS AND DISCUSSION: Mean follow-up was 20 months. No patients required use of a rigid retractor during surgery. Gross total resection was performed in 3 patients and near-total resection in 2. All patients had favorable neurologic outcome. Postoperative MRI showed no ipsilateral or contralateral brain lesions. CONCLUSION: This series suggested that meticulous DDSA allows excellent resection in selected large falcine or tentorial meningioma. The approach offered a safe and effective surgical corridor without injuring the surrounding healthy parenchyma.

Ultrasound Doppler enthesitis shows sensitivity to change after biological therapy in spondyloarthritis and psoriatic arthritis patients.

OBJECTIVE: To explore the sensitivity to change in power Doppler (PD) enthesitis in active spondyloarthritis (SpA) and psoriatic arthritis (PsA) patients. METHOD: This was a longitudinal study in patients with SpA and PsA with active disease [patients starting or switching to biological disease-modifying anti-rheumatic drugs (bDMARDs)]. The MAdrid Sonographic Enthesitis Index (MASEI) was performed at baseline and at 3 and 6 month visits. The MASEI and Outcome Measures in Rheumatology (OMERACT) PD enthesitis definitions were checked. Reliability analysis among three readers was performed with ultrasound (US)-recorded videos. RESULTS: US examinations of 25 patients were included; 16 (64%) had SpA and nine (36%) PsA. The median (interquartile range, IQR) age was 49 (41-61) years, and 13 patients (52%) were female. The median (IQR) 28-joint Disease Activity Score of 3.6 (2.3-4.2), Bath Ankylosing Spondylitis Disease Activity Index of 6.7 (6.1-7.4), and C-reactive protein value of 8.2 (1.6-20) reflected moderate to high disease activity at baseline. Both MASEI and OMERACT PD enthesitis improved significantly at 3 and 6 month follow-up (p < 0.05) and showed sensitivity to change (standard error of measurement = 0.47 and 0.61, respectively). Improvement in clinical activity outcomes was significantly associated with decreases in MASEI and OMERACT PD enthesitis counts (p < 0.05). The MASEI and OMERACT PD definitions had excellent reliability (kappa = 0.918 and 0.865, respectively). CONCLUSION: PD enthesitis significantly improved at 3 and 6 month follow-up in patients undergoing bDMARD therapy. Both MASEI and OMERACT PD US enthesitis reflect response to treatment.

Estimation of the body center of mass velocity during gait of people with transfemoral amputation from force plate data integration.

BACKGROUND: Body Center Of Mass velocity assessment is a prerequisite for several applications in prosthetic control and rehabilitation monitoring. Force plate data integration is a promising alternative to full-body quantitative analysis of segmental kinematics to estimate the velocity. Still, it remains to be implemented and validated for people with transfemoral amputation. METHODS: Two methods were used (force plate based and pelvic markers based) for Body Center Of Mass velocity estimation in a clinical context. The two methods were comparatively assessed on overground walking data of eight people with transfemoral amputation in a laboratory equipped with a motion capture system and force plates compared to reference estimation derived from a full body segmental gait analysis. The 'Methods' agreement with the reference was quantified from the Bland and Altman procedure. FINDINGS: The estimation of Body Center Of Mass velocity from force plate data integration was considered acceptable in terms of limits of agreement. In addition, the hypotheses used to determine integration constants were evaluated and shown to be reasonable as far as the walking direction is well controlled. INTERPRETATION: Results demonstrate the possibility to use the force plate method to assess the Body Center Of Mass velocity of people with transfemoral amputation for straight walking on level ground. An estimation from the velocity of pelvic markers can also be a relevant alternative as soon as the walking velocity remains low. Further investigation will deal with the impact of the errors on the computation of derived parameters such as individual limb power.

Systemic ventricular assist device support in Fontan patients: A report by ACTION.

BACKGROUND: The size of the Fontan population with end-stage heart failure is growing. In this population, heart transplantation has been the only option. This study sought to investigate the efficacy of ventricular assist device (VAD) support in Fontan patients. METHODS: We conducted a retrospective study of Fontan patients in the Advanced Cardiac Therapies Improving Outcomes Network. We evaluated patient characteristics, and the clinical and physiologic outcomes after VAD implantation. RESULTS: We identified 45 Fontan patients implanted with VAD. The average age of patients was 10 years (interquartile range: 4.5-18) and 30% were female. The majority had a morphologic right ventricle (69%), moderate or greater ventricular dysfunction (83%), and moderate or greater atrioventricular valve regurgitation (65%). The majority of implants were as a bridge to transplantation (76%), and the majority of patients were Interagency Registry for Mechanically Assisted Circulatory Support Profile 2 (56%). The most commonly employed device was the Medtronic HeartWare HVAD (56%). A total of 13 patients were discharged on device support, and 67% of patients experienced adverse events, the most common of which were neurologic (25%). At 1 year after device implantation, the rate of transplantation was 69.5%, 9.2% of patients continued to be VAD supported, and 21.3% of patients had died. Hemodynamically, VAD was effective in decreasing both Fontan and ventricular end-diastolic pressures in some individuals. CONCLUSIONS: VAD is effective in supporting patients with end-stage Fontan failure awaiting heart transplantation. Future research should focus on identifying clinical and physiologic characteristics predictive of a favorable response to VAD support.

Microprocessor prosthetic ankles: comparative biomechanical evaluation of people with transtibial traumatic amputation during standing on level ground and slope.

BACKGROUND: The compensations occurrence due to the alteration of the posture and the gait of persons with lower limb amputation is still an issue in prosthetic fitting. Recently, prosthetic feet designed to reproduce the physiological behaviour of the ankle using a microprocessor control have been commercialized to address this issue. OBJECTIVES: Investigate the relevance of these microprocessor prosthetic ankles (MPAs) in the ability of standing on both level and inclined surfaces. METHODS: Six persons with transtibial amputation usually fitted with energy storing and returning (ESR) foot tested three MPAs: Elan® Endolite (MPA1), Meridium® Ottobock (MPA2), ProprioFoot® Ossur (MPA3). Each MPA data acquisition was preceded of a 2 weeks adaptation period at home and followed by a 3-weeks wash-out period with their ESR. Lower limb angular position and moment, Centre of Pressure (CoP) position, Ground Reaction Forces (GRF) and functional scores were collected in static, on level ground and 12% inclined slope. RESULTS: MPAs allowed a better posture and a reduction of residual knee moment on positive and/or negative slope compared to ESR. Results also reflect that the MPA2 allows the best control of the CoP in all situations. CONCLUSIONS: An increased ankle mobility is associated with a better posture and balance on slope. Gait analysis would complete these outcomes. CLINICAL RELEVANCE: This study compares three MPAs to ESR analysing static posture. Static analysis on level ground and slope represents the challenging conditions people with amputation have to cope with in their daily life, especially outdoors. Having a better understanding of the three MPAs behaviour could help to adequately fit the prosthesis to each patient. Implications for rehabilitation This is a study comparing three MPAs. The static analysis in standard and constraining conditions (slope) reflects the balance of people with amputation in their daily life, especially outdoors. Having a better understanding of the behaviour of each foot could help to adequately fit the prosthesis to each patient.

Pseudomonas aeruginosa and lung function decline in patients with bronchiectasis.

OBJECTIVES: The objective of this study was to analyse lung function decline over time in bronchiectasis, along with the factors associated with it. METHODS: Spirometry was measured every year in this observational, prospective study in 849 patients from the Spanish Bronchiectasis Registry (RIBRON). The main outcome was the decline in the rate of forced expiratory volume during the first second (FEV1). To be included in this study, patients needed a baseline assessment and at least one subsequent assessment. FEV1 decline was analysed using a mixed-effects linear regression model adjusted for clinically significant variables. RESULTS: We recruited 849 bronchiectasis patients with at least two annual lung function measurements (follow-up range 1-4 years). A total of 2262 lung function tests were performed (mean 2.66 per patient, range 2-5). Mean baseline FEV1 was 1.78 L (standard deviation (SD) 0.76; 71.3% predicted). Mean age was 69.1 (SD 15.4) years; 543 (64% women. The adjusted rates of FEV1 decline were -0.98% predicted/year (95% confidence interval (CI) -2.41 to -0.69) and -31.6 (95% CI -44.4 to -18.8) mL. The annual FEV1 decline was faster in those patients with chronic bronchial infection by Pseudomonas aeruginosa (-1.37% (52.1 mL) vs -0.37% (-24.6 mL); p < 0.001), greater age, increased number of severe exacerbations in the previous year and higher baseline FEV1 value. DISCUSSION: In patients with bronchiectasis, the annual rate of FEV1 decline was -31.6 mL/year and it was faster in older patients and those with chronic bronchial infection by P. aeruginosa, increased number of previous severe exacerbations and higher baseline FEV1 value.

Bivalent engagement of endothelial surface antigens is critical to prolonged surface targeting and protein delivery in vivo.

Targeted drug delivery to the endothelium has the potential to generate localized therapeutic effects at the blood-tissue interface. For some therapeutic cargoes, it is essential to maintain contact with the bloodstream to exert protective effects. The pharmacokinetics (PK) of endothelial surface-targeted affinity ligands and biotherapeutic cargo remain a largely unexplored area, despite obvious translational implications for this strategy. To bridge this gap, we site-specifically radiolabeled mono- (scFv) and bivalent (mAb) affinity ligands specific for the endothelial cell adhesion molecules, PECAM-1 (CD31) and ICAM-1 (CD54). Radiotracing revealed similar lung biodistribution at 30 minutes post-injection (79.3% ± 4.2% vs 80.4% ± 10.6% ID/g for αICAM and 58.9% ± 3.6% ID/g vs. 47.7% ± 5.8% ID/g for αPECAM mAb vs. scFv), but marked differences in organ residence time, with antibodies demonstrating an order of magnitude greater area under the lung concentration vs. time curve (AUCinf 1698 ± 352 vs. 53.3 ± 7.9 ID/g*hrs for αICAM and 1023 ± 507 vs. 114 ± 37 ID/g*hrs for αPECAM mAb vs scFv). A physiologically based pharmacokinetic model, fit to and validated using these data, indicated contributions from both superior binding characteristics and prolonged circulation time supporting multiple binding-detachment cycles. We tested the ability of each affinity ligand to deliver a prototypical surface cargo, thrombomodulin (TM), using one-to-one protein conjugates. Bivalent mAb-TM was superior to monovalent scFv-TM in both pulmonary targeting and lung residence time (AUCinf 141 ± 3.2 vs 12.4 ± 4.2 ID/g*hrs for ICAM and 188 ± 90 vs 34.7 ± 19.9 ID/g*hrs for PECAM), despite having similar blood PK, indicating that binding strength is more important parameter than the kinetics of binding. To maximize bivalent target engagement, we synthesized an oriented, end-to-end anti-ICAM mAb-TM conjugate and found that this therapeutic had the best lung residence time (AUCinf 253 ± 18 ID/g*hrs) of all TM modalities. These observations have implications not only for the delivery of TM, but also potentially all therapeutics targeted to the endothelial surface.

[Clinical pharmacy activities coordination in an adult psychiatry unit: Clinical and medicoeconomic impact of pharmaceutical interventions]. / Coordination des activités de pharmacie clinique dans une unité de psychiatrie adulte : impact clinique et médicoéconomique des interventions pharmaceutiques.

OBJECTIVE: Coordination and evaluation of clinical pharmacy activities are necessary to optimize their achievement. Their coordination throughout patient care program was studied in an adult psychiatry unit. The purpose was to evaluate clinical and medicoeconomic impact of pharmaceutical interventions (PIs). METHOD: During five weeks, a full time pharmaceutical presence in the unit allowed medication reconciliation, medication review and multiprofessional meetings. A multiprofessional assessment of PIs impact has been achieved with the CLEO® tool and a determination of direct drug costs was realized. RESULTS: All activities combined, 190 PIs were issued, half during multiprofessional meetings, with an acceptance rate of 67.9% (100% for PIs realized during direct interactions with clinicians). All clinical pharmacy activities demonstrated relevance according to CLEO® scale's dimensions. Around 400€ were saved on direct drug costs and an avoidance of potential prolongation of hospitalization was identified in 6 PIs. CONCLUSION: PIs number, acceptance rate and evaluation results show individual impact of activities, their complementarily and the added value of their coordination. Collaboration between professionals contributed to an efficient and secure medication management. These results are reasons to optimize clinical pharmacy practice in the healthcare facility.

A standardised diagnostic approach to pituitary neuroendocrine tumours (PitNETs): a European Pituitary Pathology Group (EPPG) proposal.

The 2017 World Health Organization (WHO) classification proposes to type and subtype primary adenohypophyseal tumours according to their cell lineages with the aim to establish more uniform tumour groups. The definition of atypical adenoma was removed in favour of high-risk adenoma, and the assessment of proliferative activity and invasion was recommended to diagnose aggressive tumours. Recently, the International Pituitary Pathology Club proposed to replace adenoma with the term of pituitary neuroendocrine tumour (PitNET) to better reflect the similarities between adenohypophyseal and neuroendocrine tumours of other organs. The European Pituitary Pathology Group (EPPG) endorses this terminology and develops practical recommendations for standardised reports of PitNETs that are addressed to histo- and neuropathologists. This brief report presents the results of EPPG's consensus for the reporting of PitNETs and proposes a diagnostic algorithm.

Eritema Multiforme por Parvovirus B19 / Erithema Multiforme by Parvovirus B19

RESUMEN El Parvovirus B 19 es un virus de la familia Parvoviridae que se disemina por vía respiratoria. La infección es frecuente durante la niñez, y la seroprevalencia aumenta con la edad. Causa diversas manifestaciones clínicas según el estado inmunológico y hematológico del paciente, y la mayoría de las infecciones son asintomáticas. Se presenta el caso de una mujer adulta que presentó lesiones en diana tipo eritema multiforme e infección primaria por Parvovirus B 19.

SUMMARY Parvovirus B19 is a virus of the family Parvoviridae that spreads by respiratory route. The infection is more common during childhood and the seroprevalence increases with age. It causes a wide range of diseases according to the immunologic and hematologic patient`s status. Most of infections are asymptomatic. We report a female adult patient who presents for evaluation and management with multiple overspread eritematous asymptomatic target lesions like erythema multiforme associated with Parvovirus B 19 infection.

Ultrasonography of enthesis in psoriatic arthritis: a descriptive and reliability analysis of elemental lesions and power Doppler subtypes.

Objective: To evaluate the reliability and prevalence of enthesis ultrasound (US) elemental lesions in patients with psoriatic arthritis (PsA), using the Madrid Sonographic Enthesis Index (MASEI) and Outcome Measures in Rheumatology (OMERACT) definitions.Methods: The study included 27 PsA patients with metacarpophalangeal joint swelling. An US rheumatologist performed the MASEI examination. Prevalence and reliability of the included elemental lesions [structure, thickness, erosion, enthesophytes, power Doppler (PD), and bursae] were evaluated. In addition, three other PD definitions were checked: PD OMERACT (≤ 2 mm to the bone profile), PD enthesis-tendon (> 2 mm from the bone profile), and PD bursa. Short (3-5 s) videos of US examinations were recorded for reliability assessment.Results: MASEI and all PD definitions showed good to excellent reliability. The best reliability values were found in erosions, bursae, and PD. When present, the PD signal always appeared in more than one location of the evaluated areas. Enthesis Doppler was present in 81.5% of patients. Abnormal tendon structure and enthesophytes were the most prevalent lesions.Conclusion: MASEI demonstrates to be a reliable tool in PsA. All enthesis US Doppler definitions demonstrate to be reliable for its use in PsA with minimal differences, being PD MASEI the most sensitive in active patients.

Elucidating temporal trends in trace element exposure of green turtles (Chelonia mydas) using the toxicokinetic differences of blood and scute samples.

Blood is considered a suitable biomonitoring matrix for evaluating relatively recent exposure to environmental contaminants since abrupt changes in exposure regimes are rapidly reflected in blood. On the other hand, keratinized tissues, such as turtle scutes, are known to integrate trace element exposure over relatively long time periods. This study aimed to test the use of the differences in blood and scute to inform on the historical trace element exposure of green turtles. We propose a blood-scute kinetic model to predict how an increase in exposure would affect the concentrations in these two matrices over time. We then tested the relationship between blood and scute concentrations for 19 trace elements in two green turtle populations presumed to experience relatively constant exposure conditions. Significant log-log and linear correlations were observed between blood and scute concentrations for Co, As, Mo, Sb, and Cd. We then analysed blood-scute ratios in turtles from two coastal sites with known elevated exposure to various trace elements from previous studies. Deviations from the steady-state were clearly evident in these coastal turtles (for Co and Cd) and were consistent with the model prediction of changes in exposure. These field data provide evidence that blood-scute ratios can provide a valuable tool for examining the historical trace element exposure of turtles. We further present a method by which the general model may be refined and validated, by using data from individual turtles that had been recaptured across multiple years. Although the timeframe and number of recaptured samples available for this study were limited, the temporal changes in blood-scute ratios in these animals were generally consistent with those suggested by the model. Thus, the ratio between paired blood and scute trace element concentrations could be used to establish a temporal exposure index in turtles.

Evaluating internal exposure of sea turtles as model species for identifying regional chemical threats in nearshore habitats of the Great Barrier Reef.

Marine megafauna that forage in proximity to land can be exposed to a diverse mixture of chemicals that - individually or combined - have the potential to affect their health. Characterizing such complex exposure and examining associations with health still poses considerable challenges. The present study summarizes the development and application of novel approaches to identifying chemical hazards and their potential impacts on the health of coastal wildlife, using green sea turtles as model species. We used an epidemiological study approach to collect blood and keratinized scute samples from free-ranging turtles foraging in nearshore areas and an offshore control site. These were analyzed using a combination of non-targeted, effect-based and multi-chemical analytical screening approaches to assess internal exposure to a wide range of chemicals. The screening phase identified a suite of elements (essential and non-essential) as priority for further investigation. Many of these elements are not commonly analyzed in marine wildlife, illustrating that comprehensive screening is important where exposure is unknown or uncertain. In particular, cobalt was present at highly elevated concentrations, in the order of those known to elicit acute effects across other vertebrate species. Several trace elements, including cobalt, were correlated with clinical indicators of impaired turtle health. In addition, biomarkers of oxidative stress (e.g. 3-indolepropionic acid and lipid peroxidation products) identified in the blood of turtles showed significant correlations with clinical health markers (particularly alkaline phosphatase and total bilirubin), as well as with cobalt. To assist interpretation of trace element blood data in the absence of sufficient information on reptile toxicity, we established exposure reference intervals using a healthy control population. In addition, trace element exposure history was investigated by establishing temporal exposure indices using steady-state relationships between blood and scute. Overall, the data provide a strong argument for the notion that trace element exposure is having an impact on the health of coastal sea turtle populations.

Increased prevalence of asymptomatic vertebral fractures in HIV-infected patients over 50 years of age.

The prevalence of asymptomatic vertebral fracture in HIV-infected patients over 50 was 20%, associated with older age, male sex, longer time since HIV diagnosis, and tubular renal alterations. Vertebral fractures were independent of osteoporosis at lumbar spine, and were not predicted by the use of the FRAX equation. PURPOSE: Vertebral fractures (VF) are the hallmark of osteoporotic fractures. Our objective was to determine the prevalence of asymptomatic VF and associated factors in HIV-infected patients over 50 years, and the role of FRAX equation. METHODS: In a cross-sectional study, a diagnosis of VF was established by the semiquantitative method of Genant in thoracic and lumbar radiographs. Simultaneously, a dual X-ray absorptiometry (DXA), bone and kidney-related analytical, calcium intake, physical exercise, HIV-related factors, and FRAX estimation were evaluated. RESULTS: Overall, 128 patients (35 women, 27%) were included. Mean age was 57 years. Hypophosphatemia and tubular renal dysfunction were observed in 13 and 21%. DXA scan showed osteopenia and osteoporosis at hip in 65 and 7% of patients, and in spine in 39 and 34%, respectively. VF were observed in 26 patients (20%), with a trend to be associated with lower serum phosphate, increased alkaline phosphatase, and with lower daily calcium intake. In a multivariate analysis, older age (OR 1.2 per year; 14% of VF at 50-55; 44% at 65-70), male sex (26 vs 6%), longer time since HIV diagnosis, and renal and tubular dysfunction were the associated factors. VF were not related with osteoporosis at lumbar spine, and could not be predicted by the FRAX equation. CONCLUSIONS: The prevalence of asymptomatic vertebral fractures is high in HIV-infected patients older than 50 years, and is not identified by the presence of osteoporosis in spine neither predicted by the FRAX equation. Spine and lumbar X-rays should be routinely performed in this aging population.

Vascular endothelial effects of collaborative binding to platelet/endothelial cell adhesion molecule-1 (PECAM-1).

Targeting drugs to endothelial cells has shown the ability to improve outcomes in animal models of inflammatory, ischemic and thrombotic diseases. Previous studies have revealed that certain pairs of ligands (antibodies and antibody fragments) specific for adjacent, but distinct, epitopes on PECAM-1 enhance each other's binding, a phenomenon dubbed Collaborative Enhancement of Paired Affinity Ligands, or CEPAL. This discovery has been leveraged to enable simultaneous delivery of multiple therapeutics to the vascular endothelium. Given the known role of PECAM-1 in promoting endothelial quiescence and cell junction integrity, we sought here to determine if CEPAL might induce unintended vascular effects. Using a combination of in vitro and in vivo techniques and employing human and mouse endothelial cells under physiologic and pathologic conditions, we found only modest or non-significant effects in response to antibodies to PECAM-1, whether given solo or in pairs. In contrast, these methods detected significant elevation of endothelial permeability, pro-inflammatory vascular activation, and systemic cytokine release following antibody binding to the related endothelial junction protein, VE-Cadherin. These studies support the notion that PECAM-1-targeted CEPAL provides relatively well-tolerated endothelial drug delivery. Additionally, the analysis herein creates a template to evaluate potential toxicities of vascular-targeted nanoparticles and protein therapeutics.

Colonic Bacteroides are positively associated with trabecular bone structure and programmed by maternal vitamin D in male but not female offspring in an obesogenic environment.

BACKGROUND/OBJECTIVES: The gut microbiota is determined early in life, possibly including pregnancy. Pioneering data suggest vitamin D, a nutrient important for bone health, affects this microbiota. We found that high maternal vitamin D lowered circulating lipopolysaccharide (LPS), improved intestinal barrier and bone health in male but not female offspring in an obesogenic environment. This study determined if high maternal dietary vitamin D programs Bacteroides and Prevotella and whether this associates with bone mineral content, density and structure of male and female adult offspring fed an obesogenic diet. METHODS: C57BL/6J females received an AIN93G diet with high or low vitamin D from before mating until weaning. Post-weaning, male and female offspring remained on their respective vitamin D level or were switched and fed a high fat and sucrose diet until killing (age 7 months). Bacteroides and Prevotella were quantified in dams' feces and offspring colonic contents. LPS concentrations, bone mineral density and content, strength and structure data were integrated from our previous studies in the same mice. Spearman correlations were completed between Bacteroides and LPS, and bone outcomes. RESULTS: There was a maternal vitamin D effect on colonic Bacteroides but not Prevotella (dam diet: <0.001 and 0.735) in adult male offspring, independent of dams fecal Bacteroides before birth (P=0.998). In males, but not females, Bacteroides correlated with LPS (r=-0.488, P=0.018), trabecular femur peak load (r=0.362, P=0.033), vertebral trabecular separation (r=-0.605, P=0.006), trabecular number (r=0.614, P=0.005) and bone volume fraction (r=0.549, P=0.015). CONCLUSIONS: Dietary vitamin D programs Bacteroides in male adult offspring only, which correlated negatively with systemic inflammation and positively with bone strength and structure. This may have implications on maternal diet and nutritional guidelines targeting sexes in a different manner.